This invention relates to the manufacture of methadone and more particularly to an improved process for preparing the methadone precursor 2,2-diphenyl-4-(dimethylamino)-pentane nitrile.
Methadone hydrochloride, i.e. 6-(dimethylamino)-4,4-diphenyl-3-heptanone hydrochloride is widely used as a narcotic analgesic, particularly in clinical treatment for withdrawal from heroin addiction. Methadone is prepared by reaction of 2,2-diphenyl-4-(dimethylamino)-pentane nitrile with an ethylmagnesium halide. ##STR1## Conventionally the amino nitrile precursor is prepared by the reaction of diphenylacetonitrile with 1-(dimethylamino)-2-halopropane and base. See Schultz et al. Journal of the American Chemical Society, 69, 188 and 2458 (1947). In this reaction the base abstracts a proton from the diphenylacetonitrile and induces formation of a cyclic ethylenimmonium ion intermediate from the 1-(dimethylamino)-2-halopropane ##STR2## The carbanion can react at either of two sites on the ethylenimonium ion to produce either the desired intermediate 2,2-diphenyl-4-(dimethylamino)-propane nitrile or its isomer 2,2-diphenyl-3-methyl-4-(dimethylamino)-butyronitrile. ##STR3## When the synthesis of the intermediate is carried out, approximately equal proportions of both the methadone precursor and its isomer are formed.
In order to drive the reaction of diphenylacetonitrile and 1-(dimethylamino)-2-halopropane substantially to completion, it is necessary to azeotropically remove water from the reaction zone. A lengthy reaction period is required to azeotrope off the water and obtain the desired conversion of approximately 85%. As a consequence, the productivity of the methadone manufacturing process is relatively low.
After completion of the above-described reaction, the methadone precursor must be isolated from its isomer and other components of the reaction mixture. This is conventionally accomplished by acidifying the reaction mixture with hydrochloric acid thereby forming the hydrochlorides of both amino nitrile isomers, which then concentrate in the aqueous phase. Thereafter, the phases are separated and an oil comprising the isomers is precipitated by addition of NaOH. Separation of the isomers is carried out by dissolving the oil in isopropyl alcohol and crystallizing 2,2-diphenyl-4-(dimethylamino)-pentane nitrile from the solution.